Raltegravir of formula (I), chemically known as N-[(4-fluorophenyl)methyl]-1,6-dihydro-5-hydroxy-1-methyl-2-[1-methyl-1-[[(5-methyl-1,3,4-oxadiazol-2-yl) carbonylamino]ethyl]-6-oxo-4-pyrimidinecarboxamide is a human immunodeficiency virus (HIV) integrase strand transfer inhibitor which in combination with other antiretroviral agents is indicated for the treatment of HIV-1 infection in adult patients already undergoing treatment and are having evidence of viral replication and HIV-1 strains resistant to multiple antiretroviral agents. The potassium salt of Raltegravir having proprietary name Isentress is administered orally as a tablet of 400 mg strength.

Various researchers have attempted to synthesize the active pharmaceutical ingredient of formula (I) and its pharmaceutically acceptable salt. Journal of Medicinal Chemistry 2008, 51, 5843-5855 as well as WO 2006060730 discloses a method for the preparation of raltegravir starting from 2-amino-2-methylpropanenitrile. However, the method has a serious drawback, involving formation of up to 22% of O-methyl impurity during the N-methylation of the pyrimidinone ring with Mg(OCH3). The removal of O-methylated impurity requires several purifications involving recrystallization and/or column chromatography, which ultimately reduces the overall yield considerably. Further, the synthetic route also results in the formation of another associated impurity during the preparation of raltegravir free base due to the O-acylation of the penultimate intermediate with oxadiazole carbonylchloride. Thus the formation of several associated impurities and their removal either by chromatographic purification or by successive crystallizations results in loss of yield which ultimately makes the process unviable for commercial use.
Organic Process Research & Development 2011, 15, 73-83 provides another circuitous method for preparation of raltegravir, wherein two methods have been disclosed for the preparation of hydroxy pyrimidinone. The document mentions that the yield of hydroxy pyrimidinone is dependent on the E/Z configuration of the compound obtained by reaction of amidoxime with dimethyl acetylene dicarboxylate. Higher yield (72%) is obtained with the Z isomer while lower yield (48%) is obtained with the corresponding E-isomer. Further, the method involves additional steps of protection and deprotection of the amino and hydroxyl group thereby, making the method lengthy and less attractive for industrial scale.
The reference also reports another method for the methylation of hydroxy pyrimidinone with trimethyl sulfoxonium iodide/magnesium hydroxide without any mention about the reaction solvent and discloses that the reaction provides ≈99% of the desired N-methyl compound after prolonged heating of the reaction mixture at high temperatures, which in turn is likely to give rise to impurities.
Thus the prior art methods are associated with lengthy and circuitous synthetic routes, which not only consume more time for each batch run but also generates associated impurities thereby requiring additional steps of purification. Regulatory authorities all over the world have very stringent norms for permissible limits of such impurities in either the active ingredient or the final formulation.
Therefore, it was imperative for the synthetic chemists to control such impurities below detectable limits during synthesis and develop a route involving a cost-effective process which did not require additional steps of purification. Hence, to overcome the prior art drawbacks, the present inventors developed a new synthetic route for raltegravir, which involves lesser number of synthetic steps, controls the level of undesired impurities below permissible limits and is cost-effective, environmental friendly for convenient implementation on an industrial scale.